Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Abstract

Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

Bifunctional Anti-Non-Amyloid Component α-Synuclein Nanobodies Are Protective In Situ

“…NbSyn87 is a camelid nanobody that binds to residues 118–131 within the C-terminal region of α-Syn. This domain has been identified as the binding site for several existing protective antibodies [18]; therefore we compared two anti-C-terminal nanobodies to the VH14 anti-NAC nanobody. While both offer protection, the NAC region is clearly the more effective target in our assays.…”

Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy

“…Several other strategies to reduce αSyn aggregation have been implemented recently and support this hypothesis. Immunization has been shown to reduce αSyn inclusions in models of α-synucleinopathies and exert neuroprotection and phenotypic improvement [22]. Small molecular tweezers, such as CLR01, have been proposed to reduce αSyn aggregation linked to neuroprotection and symptom amelioration in models of PD [23].…”

Genetics of Parkinson’s disease and related disorders

“…On the other hand, passive immunotherapy offers greater control against adverse effects and enables antibody engineering for increased brain penetration, stability and lessened cellular response. Several N-terminal and C-terminal antibodies have produced exciting results by clearing α-syn, reducing its propagation and lessening motor dysfunction 91. Safety data are positive for one phase I trial with a C-terminal antibody (PRX002), which also shows significant reduction of serum-free α-syn.…”